rs2303995

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000388996.10(KCNQ3):ā€‹c.1241A>Gā€‹(p.Glu414Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0271 in 1,611,190 control chromosomes in the GnomAD database, including 1,347 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.025 ( 134 hom., cov: 33)
Exomes š‘“: 0.027 ( 1213 hom. )

Consequence

KCNQ3
ENST00000388996.10 missense

Scores

6
11

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7O:1

Conservation

PhyloP100: 3.49
Variant links:
Genes affected
KCNQ3 (HGNC:6297): (potassium voltage-gated channel subfamily Q member 3) This gene encodes a protein that functions in the regulation of neuronal excitability. The encoded protein forms an M-channel by associating with the products of the related KCNQ2 or KCNQ5 genes, which both encode integral membrane proteins. M-channel currents are inhibited by M1 muscarinic acetylcholine receptors and are activated by retigabine, a novel anti-convulsant drug. Defects in this gene are a cause of benign familial neonatal convulsions type 2 (BFNC2), also known as epilepsy, benign neonatal type 2 (EBN2). Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2014]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0017500818).
BP6
Variant 8-132163489-T-C is Benign according to our data. Variant chr8-132163489-T-C is described in ClinVar as [Benign]. Clinvar id is 21409.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-132163489-T-C is described in Lovd as [Benign].
BA1
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.165 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
KCNQ3NM_004519.4 linkuse as main transcriptc.1241A>G p.Glu414Gly missense_variant 9/15 ENST00000388996.10 NP_004510.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
KCNQ3ENST00000388996.10 linkuse as main transcriptc.1241A>G p.Glu414Gly missense_variant 9/151 NM_004519.4 ENSP00000373648 P1O43525-1

Frequencies

GnomAD3 genomes
AF:
0.0247
AC:
3752
AN:
152188
Hom.:
136
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00478
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0255
Gnomad ASJ
AF:
0.0219
Gnomad EAS
AF:
0.174
Gnomad SAS
AF:
0.0242
Gnomad FIN
AF:
0.0361
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0241
Gnomad OTH
AF:
0.0205
GnomAD3 exomes
AF:
0.0354
AC:
8886
AN:
251066
Hom.:
359
AF XY:
0.0338
AC XY:
4588
AN XY:
135682
show subpopulations
Gnomad AFR exome
AF:
0.00302
Gnomad AMR exome
AF:
0.0412
Gnomad ASJ exome
AF:
0.0255
Gnomad EAS exome
AF:
0.170
Gnomad SAS exome
AF:
0.0172
Gnomad FIN exome
AF:
0.0371
Gnomad NFE exome
AF:
0.0224
Gnomad OTH exome
AF:
0.0276
GnomAD4 exome
AF:
0.0273
AC:
39844
AN:
1458882
Hom.:
1213
Cov.:
29
AF XY:
0.0270
AC XY:
19573
AN XY:
726072
show subpopulations
Gnomad4 AFR exome
AF:
0.00305
Gnomad4 AMR exome
AF:
0.0396
Gnomad4 ASJ exome
AF:
0.0255
Gnomad4 EAS exome
AF:
0.200
Gnomad4 SAS exome
AF:
0.0169
Gnomad4 FIN exome
AF:
0.0365
Gnomad4 NFE exome
AF:
0.0219
Gnomad4 OTH exome
AF:
0.0267
GnomAD4 genome
AF:
0.0246
AC:
3747
AN:
152308
Hom.:
134
Cov.:
33
AF XY:
0.0267
AC XY:
1985
AN XY:
74482
show subpopulations
Gnomad4 AFR
AF:
0.00476
Gnomad4 AMR
AF:
0.0254
Gnomad4 ASJ
AF:
0.0219
Gnomad4 EAS
AF:
0.175
Gnomad4 SAS
AF:
0.0238
Gnomad4 FIN
AF:
0.0361
Gnomad4 NFE
AF:
0.0241
Gnomad4 OTH
AF:
0.0194
Alfa
AF:
0.0277
Hom.:
262
Bravo
AF:
0.0238
TwinsUK
AF:
0.0208
AC:
77
ALSPAC
AF:
0.0210
AC:
81
ESP6500AA
AF:
0.00340
AC:
15
ESP6500EA
AF:
0.0224
AC:
193
ExAC
AF:
0.0340
AC:
4126
Asia WGS
AF:
0.0780
AC:
271
AN:
3478
EpiCase
AF:
0.0198
EpiControl
AF:
0.0210

ClinVar

Significance: Benign
Submissions summary: Benign:7Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:2
Benign, criteria provided, single submitterclinical testingGeneDxFeb 17, 2012This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, no assertion criteria providedclinical testingGenetic Services Laboratory, University of Chicago-Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Seizures, benign familial neonatal, 2 Benign:1Other:1
not provided, no classification providedliterature onlyGeneReviews-- -
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Inborn genetic diseases Benign:1
Benign, criteria provided, single submitterclinical testingAmbry GeneticsApr 15, 2016This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign Neonatal Epilepsy Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
Benign neonatal seizures Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 01, 2024- -
not provided Benign:1
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.24
BayesDel_addAF
Benign
-0.28
T
BayesDel_noAF
Uncertain
-0.030
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.56
D;.;.;.;.
Eigen
Benign
-0.024
Eigen_PC
Benign
0.11
FATHMM_MKL
Uncertain
0.87
D
LIST_S2
Benign
0.55
T;T;T;T;T
MetaRNN
Benign
0.0018
T;T;T;T;T
MetaSVM
Benign
-0.48
T
MutationTaster
Benign
0.27
P;P;P
PrimateAI
Benign
0.44
T
PROVEAN
Uncertain
-3.1
D;.;D;D;.
REVEL
Uncertain
0.35
Sift
Benign
0.032
D;.;D;D;.
Sift4G
Benign
0.14
T;T;T;T;.
Polyphen
0.12
B;.;.;B;.
Vest4
0.50
MPC
1.1
ClinPred
0.019
T
GERP RS
4.6
Varity_R
0.20
gMVP
0.70

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs2303995; hg19: chr8-133175736; COSMIC: COSV66474926; API